Cardiovascular disease (CVD) is arguably the greatest non-infectious health care problem ever to afflict mankind. There is widespread agreement regarding the promise of stem/progenitor cells to replace cardiomyocytes after myocardial infarction (MI), but there is little agreement on how best to make these cells. Despite a population of stem/progenitor cells in residency, the human heart has little, if any, native ability to repair itself by regenerating and rebuilding muscle after MI. To make new muscle cells in the adult human heart by enhancing the function of endogenous pools or by harnessing the differentiation potential of exogenously supplied stem/progenitor cells is one of the long-term goals of NHLBI's Progenitor Cell Biology Consortium. This planning grant application sets forth the goals of our proposed UT Southwestern scientific group, to be led by Dr. Eric Olson, and outlines how our contribution will be unique and crucial to the success of the Consortium as a whole. Our approach to cardiac repair and regeneration is innovative and based on solid preliminary findings. Indeed, collectively we have been working in this field and preparing for participation in this Consortium for more than two decades. We are committed to exploring the mechanistic underpinnings of the native myocardial repair process, discovering natural barriers that prevent effective repair, and devising synthetic small molecule, HDAC-inhibitor, and miRNA-based pharmaco-therapies and strategies to overcome these barriers. The overall goal of our group will be to combine the power of miRNAs, small molecules (including HDAC inhibitors), and native stem/progenitor cell biology to dissect fundamental mechanisms that control cardiac cell fate and repair, and to exploit these new discoveries to ultimately develop novel cardio-therapeutics. We will propose two intersecting projects that will provide new starting points for therapeutic RNA and drug development, while expanding the mechanistic science of cardiac myogenesis, regeneration, and repair. If selected to advance to the next step, we will present a detailed plan to enhance the already-intensive synergy between the three PIs and the labs that will comprise the UT Southwestern group and extend this collegiality to all other groups of the Consortium. As a member of NHLBI Progenitor Cell Biology Consortium, we will make substantial and important contributions to advancing this new frontier of cardiovascular regenerative medicine.